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Functional systemic CD4 immunity is required for clinical responses to PD‐L1/PD‐1 blockade therapy
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Functional systemic CD4 immunity is required for clinical responses to PD‐L1/PD‐1 blockade therapy
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Journal Article
Functional systemic CD4 immunity is required for clinical responses to PD‐L1/PD‐1 blockade therapy
2019
Overview
The majority of lung cancer patients progressing from conventional therapies are refractory to PD‐L1/PD‐1 blockade monotherapy. Here, we show that baseline systemic CD4 immunity is a differential factor for clinical responses. Patients with functional systemic CD4 T cells included all objective responders and could be identified before the start of therapy by having a high proportion of memory CD4 T cells. In these patients, CD4 T cells possessed significant proliferative capacities, low co‐expression of PD‐1/LAG‐3 and were responsive to PD‐1 blockade
ex vivo
and
in vivo
. In contrast, patients with dysfunctional systemic CD4 immunity did not respond even though they had lung cancer‐specific T cells. Although proficient in cytokine production, CD4 T cells in these patients proliferated very poorly, strongly co‐upregulated PD‐1/LAG‐3, and were largely refractory to PD‐1 monoblockade. CD8 immunity only recovered in patients with functional CD4 immunity. T‐cell proliferative dysfunctionality could be reverted by PD‐1/LAG‐3 co‐blockade. Patients with functional CD4 immunity and PD‐L1 tumor positivity exhibited response rates of 70%, highlighting the contribution of CD4 immunity for efficacious PD‐L1/PD‐1 blockade therapy.
Synopsis
Lung cancer patients are often refractory to PD‐L1/PD‐1 blockade therapy. This study shows that patients progressing from conventional therapies that have functional CD4 T cells respond to PD‐L1/PD‐1 blockade immunotherapy, while patients with proliferative dysfunctional CD4 T cells do not respond.
Functional systemic CD4 immunity is required for objective clinical responses to PD‐L1/PD‐1 blockade therapy in human lung cancer patients.
Systemic memory CD4 T cells identify intrinsic non‐responder from potentially responder patients.
70% of patients with high baseline percentages of memory CD4 T cells and PD‐L1‐positive tumors respond to therapy.
Proliferative CD4 dysfunctionality in non‐responder patients can be overcome by PD‐1/LAG‐3 co‐blockade.
Graphical Abstract
Lung cancer patients are often refractory to PD‐L1/PD‐1 blockade therapy. This study shows that patients progressing from conventional therapies that have functional CD4 T cells respond to PD‐L1/PD‐1 blockade immunotherapy, while patients with proliferative dysfunctional CD4 T cells do not respond.
Publisher
Nature Publishing Group UK,Springer Nature
Subject
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